ASH 2021 | The association between CHIP and MGUS

So MGUS and CHIP are two distinct conditions characterized by clonality of hematopoietic cells. In the case of CHIP, clonality is at the expense of hematopoietic stem cells, and you can find it by sequencing peripheral blood of patients. In the case of MGUS, clonality is at the expense of plasma cells. And you can find it by looking at serum protein electrophoresis, because these plasma cells produce a monoclonal antibody, which is easily recognized by electrophoresis. So we’ve been knowing about MGUS for much longer than we have about CHIP, just because it’s easier to diagnose. But we now know that both conditions are quite prevalent in the elderly and they are both clonal and they both involve hematopoietic cells. So we ask the question whether there could be a correlation between MGUS and CHIP, which would imply that there could be some hierarchical relationships between clonal hematopoietic stem cells differentiating into clonal plasma cells, which then would be perhaps more prone to develop into cancer cells in multiple myeloma.

So to answer this question, what we did was to leverage a very large population based study comprising 770 elderly patients. And by elderly, I mean average age of 91 years. Well, that’s defined actually as an oldest old cohort. So because those clonal conditions are more prevalent as the age increases, we figured this would be the best setting to look to data to answer our question. So what we found was actually quite remarkable in that despite our initial hypothesis of there being a possible correlation between the two conditions, we find very few cases of individuals carrying both CHIP and MGUS. And by doing some statistics, we realized that the two conditions were actually anti-correlated rather than correlated. So it was borderline significant, but rather than being neutral, there was a tendency towards these conditions being not diagnosed together more frequently than you would expect by chance.

So this is unexpected because of the age related incidents of these conditions. There could be some biases in our cohort because patients being so elderly, there could be a bias towards female patients where MGUS is less prevalent or people who successfully made it to the age of 90 without developing any problems, so they could be selected somehow. But nevertheless, biologically our results seem to tell us that MGUS and CHIP develop as two distinct conditions through different biological pathways. And it appears that there is no correlation between the two. So of course, there are ongoing studies where we’re trying to ascertain whether having one would biologically favor developing the other. And of course, more population based studies are needed to corroborate our findings. But talking about this, there has been a recent Nature medicine paper from the Brigham group of Ben Ebert and A Niroula is the first name, where in fact CHIP was not associated with later development of MGUS and multiple myeloma, which seems to go along our findings of the two being two distinct entities.